Sains Malaysiana 48(5)(2019): 1083–1095 http://dx.doi.org/10.17576/jsm-2019-4805-17

Oxidative Status in Bipolar Disorder (BD) and Its Correlation with Age, Gender and Body Mass Index (BMI)

(Status Oksidatif dalam Gangguan Bikutub dan Kaitannya dengan Umur, Jantina dan Indeks Jisim Tubuh)

JACLYN TAN AI CHIN, GEETHA GUNASEKARAN, MOHD HANAFI AHMAD DAMANHURI, CHAN LAI FONG, LOO JIANN LIN & GOON JO AAN*

ABSTRACT

Bipolar disorder (BD) is a chronic psychiatric illness which molecular foundations have yet to be elucidated. Oxidative stress appears to be a promising field of study to understand the formation of this disease in molecular level. The objective was to investigate the oxidative status of BD and its association with age, gender and body mass index (BMI). A cross-sectional study was conducted in a tertiary university hospital in Cheras, Malaysia on 55 patients with BD diagnosed using Mini Neuropsychiatric Interview (MINI). Peripheral markers of oxidative stress which include superoxide dismutase (SOD), glutathione peroxidise (GPx), catalase (CAT), malondialdehyde (MDA) and DNA damage were examined in subjects with BD (n=55) and compared to healthy controls (n=28). BD patients had significantly higher concentrations of MDA compared to healthy controls (p

1084

normal meningkat dengan umur (p

1085

interesting to explore the oxidative stress between early and late onset of this illness. Further insights regarding oxidative stress in BD with relevance to age may potentially shed some light towards the formation of this disease. In addition, these findings may also prove to be useful for future clinical and genetic studies for this illness. In terms of gender, existing literatures proposed that it plays an important role in the clinical presentation of bipolar disorder (BD) (Diflorio & Jones 2010). Studies have found that comorbid anxiety (Benedetti et al. 2007) and eating disorders (Diflorio & Jones 2010) are more common in women with BD, while men are more prone to comorbid alcohol or drug abuse (Kawa et al. 2005; Kessing 2004; Ringen et al. 2008). The predominance of depressive and anxious symptomatology in women with BD correlates with validated findings of increased prevalence of affective morbidity in women (Kessler et al. 1993). Some studies have shown that in recent years, several pathologies involving oxidative imbalances have been underestimated in women and that those diseases progress differently by gender (Malorni et al. 2007). Furthermore, the clinical features, phenomena and evolution of BD greatly differ between men and women, particularly the course of illness, quality of life and psychosocial functioning of patients (Miquel et al. 2011; Nivoli et al. 2011). BD has also been found to be associated with increased morbidity and mortality due to general medical conditions such as metabolic syndrome, cardiovascular diseases and obesity (Kupfer 2005; Roshanaei-Moghaddam & Katon 2009). Obesity rates are found to be higher than normal across an array of psychiatric disorders including anxiety disorder, major depressive disorder, schizophrenia as well as bipolar disorder (Lopresti & Drummond 2013). Although this phenomenon is acknowledged in mental health studies and treatment, an understanding of their bi-directional relationship is still lacking. With the similarities in their dysregulated pathways in both obesity and bipolar disorder, the relationship between these two phenomenon in terms of oxidative status could show novel insights, subsequently help to fine tune interventions in complementing treatment to enhance mental health outcomes in BD patients. Age, gender and body mass index (BMI) effects on oxidative status of BD are still limited and the influence of these factors towards BD is not fully understood. In this present study, we aim to determine the oxidative status among BD patients compared to healthy controls. The BD subjects were subdivided based on age, gender and body mass index (BMI) to determine if these variables influence the oxidative status of those individuals, leading to differences in BD vulnerability.

MATERIALS AND METHODS

SUBJECTS RECRUITMENT

The protocol for this study was approved by the Ethical Committee of Universiti Kebangsaan Malaysia (UKM1.5.3.5/244/GUP-2014-048). Study participants that

includes 55 patients with BD and 27 healthy controls, age ranging from 19 years old to 74 years old were recruited from both inpatient and outpatient settings in University Kebangsaan Malaysia Medical Centre (UKMMC) between December 2015 and November 2017. The diagnosis of BD was confirmed based on the M.I.N.I. Neuropsychiatric Interview (MINI 7.0) (Van Vliet & De Beurs 2007). All subjects had given written informed consent before participating in the study. Exclusion criteria were the presence of alcohol dependence, substance misuse disorder, smoker, and terminal medical illness. Additional exclusion criteria for controls were the presence of lifetime psychiatric diagnoses as well as first and second grade relationship to relatives with psychiatric disorders.

ANTIOXIDANT ENZYMES

Blood samples of 10 mL were collected in heparinized tubes for the analysis of superoxide dismutase (SOD), glutathione reductase (GPx), and catalase (CAT) activities as well as comet assay and malondialdehyde (MDA) concentrations. Fresh whole blood was used for comet assay while the rest of the blood samples were centrifuged to separate the red blood cells from the plasma. The plasma layer was transferred into eppendorf tubes and the remaining RBC pellet were washed before being stored at -80°C freezer until time of analysis. Measurement of SOD activity was performed according to Beyer and Fridovich (1987). Hemosylate prepared was added to 1 mL of substrate solution, and the mixture was reacted with 10 μL riboflavin (0.117 mM) in a brightly lit aluminium foil lined box for 7 min. A control tube in which phosphate buffer was used in place of the sample was run in parallel, and the absorbance was measured at 560 nm. One unit of SOD was defined as the amount of enzyme that would inhibit the rate of reduction of nitro blue tetrazolium by 50% at 25°C at pH7.8. Measurement of GPx activity was determined based on the method published by Paglia and Valentine (1967). Hemolysates were first diluted with 0.8 mL distilled water and then mixed with 1 mL of cyanmethemoglobin reagent before adding to a substrate mixture. H2O2 (2.2 mM) was added into the reaction mixture and a change in absorbance for 5 min at 340 nm was recorded. For control, the same procedure was performed by replacing the hemolysate with distilled water. One unit of GPx was defined as the amount of enzyme that would oxidize 1 μmole NADPH to NADP+ per min at 25°C and pH8.0. CAT activity was determined according to the method published by Aebi (1984). The reaction was initiated with the addition of H2O2 (30 mM) to the enzyme solution. The change in absorbance was read against a blank containing 1 mL phosphate buffer instead of H2O2 and 2 mL enzyme solution. One unit of CAT was defined as the amount of enzyme that would decompose 1 μmole H2O2 per second at 25°C and pH7.0. Haemoglobin content of all hemolysates used for SOD, GPx and CAT analyses were measured by using a

1086

haemoglobin assay kit supplied by Eagle Diagnostic (USA) based on manufacturer’s guide.

DNA DAMAGE

DNA damage determination was carried out based on the comet assay protocol published by Singh et al. (1994). To prepare the slides, 5 μL fresh whole blood with 80 μL 0.6% low-melting-point agarose (LMA) was sandwiched between a layer of 0.6% normal melting-point agarose (NMA) on a frosted slide. Then, the slides were immersed in lysis solution for 1 h at 4°C to release the DNA. Next, the DNA was denatured by placing the slides in an alkaline bath to enable the expression of alkali-labeled DNA damage for 20 min at 4°C. Electrophoresis was conducted for 20 min at 4°C using 25 V and 300 mA. After electrophoresis, the slides were neutralized using 0.4 M Tris-base by a dropwise manner. Lastly, the DNA was stained with ethidium bromide (20 μg/mL) and before being analyzed using a fluorescence microscope. A total of 500 cells were analyzed for each subject, and the degree of DNA damage was categorized into normal, mildly damaged, and severely damaged DNA based on the microscopic observation of tail length of each cell shown in Figure 1.

MALONDIALDEHYDE (MDA)

Plasma MDA concentration was determined using the method published by Pilz et al. (2000). MDA standard curve was first prepared according to the manufacturer’s guide. For alkaline hydrolysis of protein-bound MDA, 50 µL of 6 M sodium hydroxide was added to 0.25 mL of plasma, and the sample was incubated for 1 h in a 60°C water bath. The hydrolyzed sample was acidified with

0.125 mL of 35% perchloric acid. After centrifugation at 3000 rpm, 0.25 mL of supernatant was mixed with 25 μL 2,4-dinitrophenylhydrazine (DNPH) solution and incubated for 10 min. A 30 μL volume of the reaction mixture was directly injected into the high performance liquid chromatography system (HPLC). Analytical HPLC separations were performed with a variable wavelength ultraviolet detector operated at 310 nm on a 3.9 ×150 mm C18 column.

STATISTICAL ANALYSIS

Statistical analysis was performed using SPSS 23.0 (IBM, Armonk, USA). The results are expressed as means ± SD, and p

1087

RESULTS

The demographic data of the study participants with BD and healthy controls are shown in Table 1. Due to the limitation of research funding, subjects that were successfully recruited were not age- and sex-matched with cases. The average age for subjects with BD was generally older as compared to the controls while the number of females were more than males in BD.

There were no significant differences in SOD activity when compared between male and female BD subjects (Figure 2). Either male nor female BD subjects had differences in the activity of SOD when compared to their respective controls. BD subject aged ≥40 had similar SOD activity to those aged ≤39. Comparisons within the similar age groups also showed no significant differences in the activity of SOD. However, SOD activity was significantly higher in BD patients with BMI ≤ 24.9 compared to ≥ 25.

FIGURE 2. SOD activity in BD patients and normal controls. (A) SOD activity was comparable between BD patients and controls, (B) SOD activity were similar between males and females BD patients as well as between patients and controls of the same gender, (B)

SOD activity did not show significant difference between BD patients aged ≤39 and ≥40 as well as between patients and controls of the same age group, (C) SOD activity was significantly higher in BD patients with BMI ≤ 24.9 compared to BMI ≥ 25 (p

1088

The activity of SOD was similar between BD and control when comparison was made within the same BMI groups. As for CAT activity, significantly higher enzyme activity was found in BD patients compared to controls (Figure 3). Further grouping by gender showed that CAT activity was comparable between male and female BD patients. In addition, no significant differences were found in the activity of CAT when comparison was made between BD and control subjects within a single gender. The activity of this enzyme was also similar between BD patients aged ≤39 and ≥40. Patients within the same age groups had comparable CAT activity to the controls. Overweight BD patients with BMI ≥25 had similar level of CAT activity compared to BD patients with BMI ≤24.9. Patients within the same BMI groups also had comparable levels of CAT activity to the controls.

BD patients had no significant differences in GPx activity compared with the controls (Figure 4). The activity of this enzyme also showed no significant differences when comparisons were made between BD patients and control grouped according to gender, age and BMI was found when compared between all groups. Similarly, no marked differences were found when BD patients were compared to the controls within the same gender, age group and BMI group. BD patients had significantly higher concentrations of MDA compared to healthy controls (p

1089

Percentage of normal DNA was significantly lower in BD patients compared to controls (p

1090

FIGURE 5. MDA concentration in BD patients and normal controls. (A) MDA concentration was significantly higher in BD patients compared to controls (p

1091

FIGURE 6. Percentage of DNA damage in BD patients and controls (A) Percentage of normal DNA was significantly higher in controls compared to BD (p

1092

radial diffusivity differences, could be explained by the variation in lipid hydroperoxide levels, indicating that peripheral lipid peroxidation levels were associated with white matter abnormalities. In this study, DNA damage was also found to be markedly higher in BD compared to control. This is parallel with the findings from previous studies using similar methods (Andreazza et al. 2007; Frey et al. 2007). The effect of DNA damage in BD may be in concordance to the elevated morbidity and mortality risk due to general medical conditions such as obesity (Gao et al. 2004) and cardiovascular disease (Demirbag et al. 2005), since these conditions are more prevalent in BD compared to the general population (Kupfer 2005; Lopresti & Drummond 2013). Thus, further analysis was performed to determine whether increased BMI has significant influence on oxidative status in BD compared to control. BMI classification was used according to the recommendation by WHO. Because none of the subjects were underweight (

1093

severe psychiatric symptoms of the younger group during sampling in this study may have contributed to higher percentage of DNA damage compared to the group aged 40 and above. On the other hand, no significant correlation has been found on age and BMI with MDA concentration. However, this data is limited to the small sample size adopted in this study as well as unequal distribution of age and gender of subjects in BD and control groups. Further investigations involving larger sample size are necessary to illustrate the underlying mechanisms of oxidative stress pathways in the progression of BD, as well as moderating the influence of gender, age and anthropometric parameters in BD.

CONCLUSION

Our findings support the preliminary evidence of altered oxidative status in BD. Based on the results, age and BMI are found to be associated with the oxidative status of BD patients regardless of gender.

ACKNOWLEDGEMENTS

This research is funded by Universiti Kebangsaan Malaysia Research University Grant GUP-2014-048. We would like to thank our subjects for their dedication and support.

REFERENCES

Aebi, H. 1984. Catalase in vitro. Methods in Enzymology 105: 121-126.

Andreazza, A.C., Gildengers, A., Rajji, T.K., Zuzarte, P.M.L., Mulsant, B.H. & Young, L.T. 2015. Oxidative stress in older patients with bipolar disorder. The American Journal of Geriatric Psychiatry: Official Journal of the American Association for Geriatric Psychiatry 23(3): 314-319.

Andreazza, A.C., Kauer-Sant’anna, M., Frey, B.N., Bond, D.J., Kapczinski, F., Young, L.T. & Yatham, L.N. 2008. Oxidative stress markers in bipolar disorder: A meta-analysis. Journal of Affective Disorders 111(2): 135-144.

Andreazza, A.C., Frey, B.N., Erdtmann, B., Salvador, M., Rombaldi, F., Santin, A., Goncalves, C.A. & Kapczinski, F. 2007. DNA damage in bipolar disorder. Psychiatry Research 153(1): 27-32.

Banerjee, U., Dasgupta, A., Rout, J.K. & Singh, O.P. 2012. Effects of lithium therapy on Na+-K+-atpase activity and lipid peroxidation in bipolar disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry 37(1): 56-61.

Benedetti, A., Fagiolini, A., Casamassima, F., Mian, M.S., Adamovit, A., Musetti, L., Lattanzi, L. & Cassano, G.B. 2007. Gender differences in bipolar disorder type 1: A 48-week prospective follow-up of 72 patients treated in an italian tertiary care center. The Journal of Nervous and Mental Disease 195(1): 93-96.

Bengesser, S.A., Lackner, N., Birner, A., Fellendorf, F.T., Platzer, M., Mitteregger, A., Unterweger, R., Reininghaus, B., Mangge, H., Wallner-Liebmann, S.J., Zelzer, S., Fuchs, D., Mcintyre, R.S., Kapfhammer, H.P. & Reininghaus, E.Z. 2015. Peripheral markers of oxidative stress and antioxidative defense in euthymia of bipolar disorder: Gender and obesity effects. Journal of Affective Disorders 172: 367-374.

Berk, M., Copolov, D.L., Dean, O., Lu, K., Jeavons, S., Schapkaitz, I., Anderson-Hunt, M. & Bush, A.I. 2008. N-acetylcysteine for depressive symptoms in bipolar disorder: A double-blind randomized placebo-controlled trial. Biological Psychiatry 64(6): 468-475.

Berk, M., Kapczinski, F., Andreazza, A., Dean, O., Giorlando, F., Maes, M., Yücel, M., Gama, C., Dodd, S. & Dean, B. 2011. Pathways underlying neuroprogression in bipolar disorder: Focus on inflammation, oxidative stress and neurotrophic factors. Neuroscience & Biobehavioral Reviews 35(3): 804-817.

Beyer, W.F. & Fridovich, I. 1987. Assaying for superoxide dismutase activity: Some large consequences of minor changes in conditions. Analytical Biochemistry 161(2): 559-566.

Brown, N.C., Andreazza, A.C. & Young, L.T. 2014. An updated meta-analysis of oxidative stress markers in bipolar disorder. Psychiatry Research 218(1): 61-68.

Chin, S.F., Ibahim, J., Makpol, S., Abdul Hamid, N.A., Abdul Latiff, A., Zakaria, Z., Mazlan, M., Mohd Yusof, Y.A., Abdul Karim, A. & Wan Ngah, W.Z. 2011. Tocotrienol rich fraction supplementation improved lipid profile and oxidative status in healthy older adults: A randomized controlled study. Nutrition & Metabolism 8: 42.

Chin, S.F., Hamid, N.A., Latiff, A.A., Zakaria, Z., Mazlan, M., Mohd Yusof, Y.A., Abdul Karim, A., Ibahim, J., Hamid, Z. & Wan Ngah, W.Z. 2008. Reduction of DNA damage in older healthy adults by Tri E Tocotrienol supplementation. Nutrition 24(1): 1-10.

Choy, K.H., Dean, O., Berk, M., Bush, A.I. & van den Buuse, M. 2010. Effects of N-acety-lcysteine treatment on glutathione depletion and a short-term spatial memory defcit in 2-cyclohexene-1-one-treated rats. European Journal of Pharmacology 649(1-3): 224-228.

De Sousa, R.T., Zarate, C.A., Zanetti, M.V., Costa, A.C., Talib, L.L., Gattaz, W.F. & Machado-Vieira, R. 2014. Oxidative stress in early stage bipolar disorder and the association with response to lithium. Journal of Psychiatric Research 50: 36-41.

Dean, O., Bush, A.I., Berk, M., Copolov, D.L. & van den Buuse, M. 2009. Glutathione depletion in the brain disrupts short-term spatial memory in the Y-maze in rats and mice. Behavioural Brain Research 198(1): 258-262.

Demirbag, R., Yilmaz, R. & Kocyigit, A. 2005. Relationship between DNA damage, total antioxidant capacity and coronary artery disease. Mutatation Research 570(2): 197-203.

Diflorio, A. & Jones, I. 2010. Is sex important? Gender differences in bipolar disorder. International Review of Psychiatry 22(5): 437-452.

Dröge, W. 2002. Free radicals in the physiological control of cell function. Physiological Reviews 82: 47-95.

Elhaik, E. & Zandi, P. 2015. Dysregulation of the Nf-Kb pathway as a potential inducer of bipolar disorder. Journal of Psychiatric Research 70: 18-27.

Fernandes, B.S., Gama, C.S., Maria Ceresér, K., Yatham, L.N., Fries, G.R., Colpo, G., De Lucena, D., Kunz, M., Gomes, F.A. & Kapczinski, F. 2011. Brain-derived neurotrophic factor as a state-marker of mood episodes in bipolar disorders: A systematic review and meta-regression analysis. Journal of Psychiatric Research 45(8): 995-1004.

Frey, B.N., Andreazza, A.C., Houenou, J., Jamain, S., Goldstein, B.I., Frye, M.A., Leboyer, M., Berk, M., Malhi, G.S. &

1094

Lopez-Jaramillo, C. 2013. Biomarkers in bipolar disorder: A positional paper from the international society for bipolar disorders biomarkers task force. Australian and New Zealand Journal of Psychiatry 47(4): 321-332.

Frey, B.N., Andreazza, A.C., Kunz, M., Gomes, F.A., Quevedo, J., Salvador, M., Gonçalves, C.A. & Kapczinski, F. 2007. Increased oxidative stress and DNA damage in bipolar disorder: A twin-case report. Progress in Neuro-Psychopharmacology & Biological Psychiatry 31(1): 283-285.

Gao, D., Wei, C., Chen, L., Huang, J., Yang, S. & Diehl, A.M. 2004. Oxidative DNA damage and DNA repair enzyme expression are inversely related in murine models of fatty liver disease. American Journal of Physiology Gastrointestinal & Liver Physiology 287(5): G1070-G1077.

Gil, P., Fariñas, F., Casado, A. & López-Fernández, E. 2002. Malondialdehyde: A possible marker of ageing. Gerontology 48(4): 209-214.

Góth, L. & Nagy, T. 2013. Inherited catalase deficiency: Is it benign or a factor in various age related disorders? Mutation Research 753(2): 147-154.

Grande, I., Magalhaes, P.V., Kunz, M., Vieta, E. & Kapczinski, F. 2012. Mediators of allostasis and systemic toxicity in bipolar disorder. Physiology & Behaviour 106(1): 46-50.

Haouala, A.B., Amamou, B., Allègue, M., Zaafrane, F. & Gaha, F. 2016. Age at onset of bipolar disorders: Clinical implication and prognosis of early and late onset. European Neuropsychopharmacology 26: S429.

Ighodaro, O.M. & Akinloye, O.A. 2017. First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): Their fundamental role in the entire antioxidant defence grid. Alexandria Journal of Medicine 54(4): 287-293.

Kapczinski, F., Dal-Pizzol, F., Teixeira, A.L., Magalhaes, P.V., Kauer-Sant’anna, M., Klamt, F., Moreira, J.C., De Bittencourt Pasquali, M.A., Fries, G.R., Quevedo, J., Gama, C.S. & Post, R. 2011. Peripheral biomarkers and illness activity in bipolar disorder. Journal of Psychiatric Research 45(2): 156-161.

Kawa, I., Carter, J.D., Joyce, P.R., Doughty, C.J., Frampton, C.M., Elisabeth Wells, J., Walsh, A.E. & Olds, R.J. 2005. Gender differences in bipolar disorder: Age of onset, course, comorbidity, and symptom presentation. Bipolar Disorders 7(2): 119-125.

Kessing, L.V. 2004. Gender differences in the phenomenology of bipolar disorder. Bipolar Disorders 6(5): 421-425.

Kessler, R.C., Mcgonagle, K.A., Swartz, M., Blazer, D.G. & Nelson, C.B. 1993. Sex and depression in the national comorbidity survey I: Lifetime prevalence, chronicity and recurrence. Journal of Affective Disorders 29(2-3): 85-96.

Kim, G.H., Kim, J.E., Rhie, S.J. & Yoon, S. 2015. The role of oxidative stress in neurodegenerative diseases. Experimental Neurobiology 24(4): 325-340.

Kraepelin, E. 1921. Manic depressive insanity and paranoia. The Journal of Nervous & Mental Disease 53(4): 350.

Kuloglu, M., Ustundag, B., Atmaca, M., Canatan, H., Tezcan, A.E. & Cinkilinc, N. 2002. Lipid peroxidation and antioxidant enzyme levels in patients with schizophrenia and bipolar disorder. Cell Biochemistry & Function 20(2): 171-175.

Kunz, M., Gama, C.S., Andreazza, A.C., Salvador, M., Ceresér, K.M., Gomes, F.A., Belmonte-De-Abreu, P.S., Berk, M. & Kapczinski, F. 2008. Elevated serum superoxide dismutase and thiobarbituric acid reactive substances in different phases of bipolar disorder and in schizophrenia. Progress

in Neuro-Psychopharmacology & Biological Psychiatry 32(7): 1677-1681.

Kupfer, D.J. 2005. The increasing medical burden in bipolar disorder. JAMA 293(20): 2528-2530.

Laursen, T.M. 2011. Life expectancy among persons with schizophrenia or bipolar affective disorder. Schizophrenia Research 131(1-3): 101-104.

Lewis, P., Stefanovic, N., Pete, J., Calkin, A.C., Giunti, S., Thallas-Bonke, V., Jandeleit-Dahm, K.A., Allen, T.J., Kola, I., Cooper, M.E. & de Haan, J.B. 2007. Lack of the antioxidant enzyme glutathione peroxidase-1 accelerates atherosclerosis in diabetic apolipoprotein E-Deficient mice. Circulation 115: 2178-2187.

Lopresti, A.L. & Drummond, P.D. 2013. Obesity and psychiatric disorders: Commonalities in dysregulated biological pathways and their implications for treatment. Progress in Neuro-Psychopharmacology & Biological Psychiatry 45: 92-99.

Magalhaes, P.V., Jansen, K., Pinheiro, R.T., Colpo, G.D., Da Motta, L.L., Klamt, F., Da Silva, R.A. & Kapczinski, F. 2012. Peripheral oxidative damage in early-stage mood disorders: A nested population-based case-control study. International Journal of Neuropsychopharmacology 15(8): 1043-1050.

Mahadik, S.P., Evans, D. & Lal, H. 2001. Oxidative stress and role of antioxidant and Ω-3 essential fatty acid supplementation in schizophrenia. Progress in Neuro-Psychopharmacology & Biological Psychiatry 25(3): 463-493.

Malaysian Psychiatric Association, M.P.A. 2007. Malaysian Consensus Statement for the Treatment of Bipolar Disorder.

Malorni, W., Campesi, I., Straface, E., Vella, S. & Franconi, F. 2007. Redox features of the cell: A gender perspective. Antioxidants & Redox Signaling 9(11): 1779-1802.

Mcglashan, T.H. 1988. Adolescent versus adult onset of mania. American Journal of Psychiatry 145(2): 221-223.

Merikangas, K.R., Jin, R., He, J.P., Kessler, R.C., Lee, S., Sampson, N.A., Viana, M.C., Andrade, L.H., Hu, C., Karam, E.G., Ladea, M., Medina-Mora, M.E., Ono, Y., Posada-Villa, J., Sagar, R., Wells, J.E. & Zarkov, Z. 2011. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Archives of General Psychiatry 68(3): 241-251.

Merikangas, K.R., Akiskal, H.S., Angst, J., Greenberg, P.E., Hirschfeld, R.M., Petukhova, M. & Kessler, R.C. 2007. Lifetime and 12-month prevalence of bipolar spectrum disorder in the national comorbidity survey replication. Archives of General Psychiatry 64(5): 543-552.

Miquel, L., Roncero, C., Lopez-Ortiz, C. & Casas, M. 2011. Epidemiological and diagnostic axis i gender differences in dual diagnosis patients. Adicciones 23(2): 165-172.

Nivoli, A.M.A., Pacchiarotti, I., Rosa, A.R., Popovic, D., Murru, A., Valenti, M., Bonnin, C.M., Grande, I., Sanchez-Moreno, J., Vieta, E. & Colom, F. 2011. Gender differences in a cohort study of 604 bipolar patients: The role of predominant polarity. Journal of Affective Disorders 133(3): 443-449.

O’brien, S.M., Scully, P., Scott, L.V. & Dinan, T.G. 2006. Cytokine profiles in bipolar affective disorder: Focus on acutely ill patients. Journal of Affective Disorders 90(2): 263-267.

Olusi, S. 2002. Obesity is an independent risk factor for plasma lipid peroxidation and depletion of erythrocyte cytoprotectic enzymes in humans. International Journal of Obesity 26(9): 1159-1164.

1095

Ozata, M., Mergen, M., Oktenli, C., Aydin, A., Sanisoglu, S.Y., Bolu, E., Yilmaz, M.I., Sayal, A., Isimer, A. & Ozdemir, I.C. 2002. Increased oxidative stress and hypozincemia in male obesity. Clinical Biochemistry 35(8): 627-631.

Ozcan, M.E., Gulec, M., Ozerol, E., Polat, R. & Akyol, O. 2004. Antioxidant enzyme activities and oxidative stress in affective disorders. International Clinical Psychopharmacology 19(2): 89-95.

Paglia, D.E. & Valentine, W.N. 1967. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. Journal of Laboratory & Clinical Medicine 70(1): 158-169.

Pilz, J., Meineke, I. & Gleiter, C. 2000. Measurement of free and bound malondialdehyde in plasma by high-performance liquid chromatography as the 2,4-dinitrophenylhydrazine derivative. Journal of Chromatography B: Biomedical Sciences & Applications 742(2): 315-325.

Ranjekar, P.K., Hinge, A., Hegde, M.V., Ghate, M., Kale, A., Sitasawad, S., Wagh, U.V., Debsikdar, V.B. & Mahadik, S.P. 2003. Decreased antioxidant enzymes and membrane essential polyunsaturated fatty acids in schizophrenic and bipolar mood disorder patients. Psychiatry Research 121(2): 109-122.

Ringen, P., Lagerberg, T., Birkenaes, A., Engn, J., Faerden, A., Jonsdottir, H., Nesvåg, R., Friis, S., Opjordsmoen, S. & Larsen, F. 2008. Differences in prevalence and patterns of substance use in schizophrenia and bipolar disorder. Psychological Medicine 38(09): 1241-1249.

Rosa, A.R., Singh, N., Whitaker, E., de Brito, M., Lewis, A.M., Vieta, E., Churchill, G.C., Geddes, J.R. & Goodwin, G.M. 2014. Altered plasma glutathione levels in bipolar disorder indicates higher oxidative stress; A possible risk factor for illness onset despite normal brain-derived neurotrophic factor (BDNF) levels. Psychological Medicine 4(11): 2409-2418.

Roshanaei-Moghaddam, B. & Katon, W. 2009. Premature mortality from general medical illnesses among persons with bipolar disorder: A review. Psychiatric Services 60(2): 147-156.

Saetre, P., Vares, M., Werge, T., Andreassen, O.A., Arinami, T., Ishiguro, H., Nanko, S., Tan, E.C., Han, D.H. & Roffman, J.L. 2011. Methylenetetrahydrofolate reductase (Mthfr) C677t and A1298c polymorphisms and age of onset in schizophrenia: A combined analysis of independent samples. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 156(2): 215-224.

Sarangarajan, R., Meera, S., Rukkumani, R., Sankar, P. & Anuradha, G. 2017. Antioxidants: Friend or foe? Asian Pacific Journal of Tropical Medicine 10(12): 1111-1116.

Savas, H.A., Gergerlioglu, H.S., Armutcu, F., Herken, H., Yilmaz, H.R., Kocoglu, E., Selek, S., Tutkun, H., Zoroglu, S.S. & Akyol, O. 2006. Elevated serum nitric oxide and superoxide dismutase in euthymic bipolar patients: Impact of past episodes. The World Journal of Biological Psychiatry 7(1): 51-55.

Selek, S., Savas, H.A., Gergerlioglu, H.S., Bulbul, F., Uz, E. & Yumru, M. 2008. The course of nitric oxide and superoxide dismutase during treatment of bipolar depressive episode. Journal of Affective Disorders 107(1-3): 89-94.

Singh, N., Stephens, R. & Schneider, E. 1994. Modifications of alkaline microgel electrophoresis for sensitive detection of DNA damage. International Journal of Radiation Biology 66(1): 23-28.

Swartz, H.A. & Fagiolini, A. 2012. Cardiovascular disease and bipolar disorder: Risk and clinical implications. Journal of Clinical Psychiatry 73(12): 1563-1565.

Uher, R. 2014. Gene-environment interactions in severe mental illness. Frontiers in Psychiatry 5: 48.

Van Vliet, I.M. & De Beurs, E. 2007. The MINI-international neuropsychiatric interview. A brief structured diagnostic psychiatric interview for DSM-IV en ICD-10 psychiatric disorders. Tijdschrift voor Psychiatrie 49(6): 393-397.

Versace, A., Andreazza, A.C., Young, L., Fournier, J.C., Almeida, J.R., Stiffler, R.S., Lockovich, J.C., Aslam, H.A., Pollock, M.H. & Park, H. 2014. Elevated serum measures of lipid peroxidation and abnormal prefrontal white matter in euthymic bipolar adults: Toward peripheral biomarkers of bipolar disorder. Molecular Psychiatry 19(2): 200-208.

Wiener, C., Rassier, G.T., Kaster, M.P., Jansen, K., Pinheiro, R.T., Klamt, F., Magalhães, P.V., Kapczinski, F., Ghisleni, G. & Da Silva, R.A. 2014. Gender-based differences in oxidative stress parameters do not underlie the differences in mood disorders susceptibility between sexes. European Psychiatry 29(1): 58-63.

Department of BiochemistryFaculty of MedicineUniversiti Kebangsaan Malaysia Medical CenterJalan Yaacob Latif, Bandar Tun Razak56000 Cheras, Kuala Lumpur, Federal TerritoryMalaysia

*Corresponding author; email: joaan@ukm.edu.my

Received: 23 August 2017Accepted: 25 September 2018